TitleStructure-binding activity relations of amphiphilic polymers and macrophage scavenger receptors
NamePlourde, Nicole M. (author), Moghe, Prabhas V (chair), Roth, Charles (internal member), Uhrich, Kathryn E (internal member), Welsh, William J (outside member), Rutgers University, Graduate School - New Brunswick,
SubjectChemical and Biochemical Engineering,
Low density lipoproteins,
DescriptionScavenger receptors mediate the uptake of oxidized low density lipoprotein (oxLDL), leading to cholesterol accumulation and the development of atherosclerosis. A promising avenue of interest in the treatment of cardiovascular disease is the use of a scavenger receptor inhibitor. To this end, a series of polymers were designed based on a mucic acid backbone, aliphatic acid arms and polyethylene glycol tail. Molecular modeling and docking approaches were used to understand the structure-activity relationship (SAR) between the polymers and scavenger receptor class A (SR-A). The polymers containing hydrophobic-bound carboxylate groups were the most favorable binders to the SR-A model as well as the most efficient inhibitors of oxLDL accumulation. Mutant SR-A models were generated by replacing charged residues with alanine. All charged residues in the region were necessary, with Lys60, Lys63 and Lys66 having the greatest effect on binding. However, binding was not mediated by charge alone and the polymer hydrophobic domain adjacent to the carboxylate group was found to be essential. Based on these findings from Chapter 2, the next chapter focused on the polymer backbone. Polymer models were designed to investigate the influence of backbone stereochemistry, cyclic versus linear backbone, and aromatic versus aliphatic backbone. Molecular modeling and docking results indicate the ability of the backbone to favorably position the side chains and “lock” the ligand into position. In vitro results followed those seen in the modeling predictions, with two polymers showing promise. Thus, minute changes in polymer structures can sensitively affect SR-A binding affinities and modulate the competitive inhibition of oxLDL uptake. This thesis also investigated the potential of amphiphilic polymers to target scavenger receptors and deliver a hydrophobic model drug reversing cholesterol accumulation. The polymers encapsulated hydrophobic agonist (GW3965) against nuclear Liver-X receptor α (LXR), which significantly increased the drug uptake over non-polymer delivery. In combination with the encapsulated LXR-agonist, the polymers reduced oxLDL by 88% in vitro. Thus, the thesis findings suggest that the system of amphiphilic polymers exhibited significant tunability for scavenger receptor targeting, which can be exploited both for inhibition of cholesterol uptake as well as modulating cholesterol trafficking.
NoteIncludes bibliographical references
Noteby Nicole M. Plourde
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.